US4065472A - 5-(2-Carboxythiophen-5-yl)-16-aryloxy-α-tetranor-ω-tetranorprostaglandins - Google Patents

5-(2-Carboxythiophen-5-yl)-16-aryloxy-α-tetranor-ω-tetranorprostaglandins Download PDF

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US4065472A
US4065472A US05/617,481 US61748175A US4065472A US 4065472 A US4065472 A US 4065472A US 61748175 A US61748175 A US 61748175A US 4065472 A US4065472 A US 4065472A
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trans
hydroxy
carboxythiophen
acid
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Thomas K. Schaaf
Jasjit Singh Bindra
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Pfizer Inc
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Priority to GB38949/76A priority patent/GB1508925A/en
Priority to CA261,914A priority patent/CA1085832A/en
Priority to DK435276A priority patent/DK435276A/da
Priority to BE1007651A priority patent/BE846650A/xx
Priority to JP51117079A priority patent/JPS5242872A/ja
Priority to FR7629245A priority patent/FR2325371A1/fr
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Priority to NL7610761A priority patent/NL7610761A/xx
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
    • C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
    • C07F9/655345—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring

Definitions

  • This invention relates to certain novel analogs of the naturally occurring prostaglandins.
  • it relates to novel 5-(2-carboxythiophen-5-yl)-16-aryloxy- ⁇ -tetranor- ⁇ -tetranorprostaglandins and various novel intermediates useful in their preparation.
  • the prostaglandins are C-20 unsaturated fatty acids which exhibit diverse physiological effects.
  • Each of the known, naturally occurring prostaglandins is derived from prostanoic acid which has the structure and position numbering: ##STR1## [Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), and references cited therein.]
  • a systematic name for prostanoic acid is 7-[(2 ⁇ -octyl)-cyclopent-1 ⁇ -yl]heptanoic acid.
  • PGA 2 has the structure: ##STR2##
  • PGB 2 has the structure: ##STR3##
  • PGE 2 has the structure: ##STR4##
  • PGF 2 ⁇ has the structure: ##STR5##
  • PGF 2 ⁇ has the structure: ##STR6##
  • Each of the PG 1 prostaglandins, PGE 1 , PGF 1 ⁇ , PGF 1 ⁇ , PGA 1 , and PGB 1 has a structure the same as the corresponding PG 2 compound except that the cis double bond between C-5 and C-6 is replaced by a single bond.
  • PGA 1 has the structure: ##STR7##
  • the PG 0 compounds are those in which there are no double bonds in either side chain.
  • PGE 0 has the structure ##STR8##
  • Molecules of the known prostaglandins each have several centers of asymmetry, and can exist in racemic (optically inactive) form and in either of the two enantiomeric (optically active) forms, i.e., the dextrorotatory and levorotatory forms.
  • each structure represents the particular optically active form of the prostaglandin which is obtained from certain mammalian tissues, for example, sheep vesicular glands, swine lung, or human seminal plasma, or by carbonyl and/or double bond reduction of that prostaglandin.
  • the mirror image or optical antipode of each of the above structures represents the other enantiomer of that prostaglandin.
  • the optical antipode of PGF 2 ⁇ (ent-PGF 2 ⁇ ) is drawn as ##STR9##
  • the racemic form of a prostaglandin contains equal numbers of a particular stereoisomer and its mirror image.
  • the symbols "rac" or "dl” will precede the prostaglandin name.
  • Two structures are needed to represent a racemate.
  • the structure of dl-PGF 2 ⁇ is properly represented as an equimolar mixture of PGF 2 ⁇ and ent-PGF 2 ⁇ .
  • PGE 1 , PGE 2 , PGF 1 ⁇ and the like as used herein will mean that stereoisomer with the same absolute configuration as the corresponding prostaglandin found in mammalian tissue.
  • the absolute configuration at all of the above-mentioned centers of asymmetry is inverted.
  • the configuration is inverted at one or more but not all of the centers.
  • the absolute configuration of the 15-hydroxy group in 15-epi-PGF 2 ⁇ is the R configuration and is shown as ##STR10## It will be noted that only the configuration at the 15-position is inverted and that at the other centers of asymmetry, namely the 8-, 9-, 11- and 12-positions, the absolute configuration is the same as that in the naturally-occurring mammalian PGF 2 ⁇ .
  • Mixtures of epimers may also exist for instance, if 15-keto-PGF 2 ⁇ is reduced with zinc borohydride or a hindered alkyl borohydride, the resulting product is a racemic mixture of 15 ⁇ -hydroxy and 15 ⁇ -hydroxy-PGF 2 ⁇ .
  • PGE 1 , PGE 2 , and the corresponding PGF.sub. ⁇ , PGF.sub. ⁇ , PGA, and PGB compounds, and many of their derivatives such as the esters, acylates and pharmacologically acceptable salts, are extremely potent inducers of various biological responses. These compounds are, therefore, potentially useful for pharmacological purposes.
  • Prostaglandins are useful to prevent, control, or alleviate a wide variety of diseases and undesirable physiological conditions in avians and mammals, including humans, useful domestic animals, pets, and zoological specimens, and in laboratory animals, for example, mice, rats, rabbits, and monkeys.
  • these compounds are useful in mammals, including man, as bronchodilators [Cuthbert, Brit. Med. J., 4: 723-726, 1969].
  • the compounds are used in a dose range of about 10 ⁇ g. to about 10 mg. per ml. of a pharmacologically suitable liquid vehicle or as an aerosol spray, both for topical application.
  • the PGE compounds are useful in the treatment of asthma because of their activity as bronchodilators and/or as inhibitors or mediators, such as SRS-A, and histamine which are released from cells activated by an antigen-antibody complex. Thus, these compounds control spasm and facilitate breathing in conditions such as bronchial asthma, bronchitis, bronchiectasis, pneumonia and emphysema.
  • these compounds are administered in a variety of routes in a number of dosage forms, e.g., orally in the form of tablets, capsules, or liquids; rectally in the form of suppositories; parenterally with intravenous administration being preferred in emergency situations; by inhalation in the form of aerosols or solutions for nebulizers; or by insufflation in the form of powder.
  • dosage forms e.g., orally in the form of tablets, capsules, or liquids; rectally in the form of suppositories; parenterally with intravenous administration being preferred in emergency situations; by inhalation in the form of aerosols or solutions for nebulizers; or by insufflation in the form of powder.
  • Doses in the range of about 0.01 to 5 mg. per kg. of body weight are used 1 to 4 times a day.
  • prostaglandins can also be combined advantageously with other anti-asthmatic agents, such as sympathomimetics (isoproterenol, phenylephrine, ephedrine, etc.); xanthine derivatives (theophylline and aminophyllin); and corticosteroids (ACTH and prednisolone).
  • sympathomimetics isoproterenol, phenylephrine, ephedrine, etc.
  • xanthine derivatives theophylline and aminophyllin
  • corticosteroids corticosteroids
  • the PGE and PGA compounds are useful in mammals, including man and animals to reduce and control excessive gastric secretion, thereby reducing or avoiding gastrointestinal ulcer formation, and accelerating the healing of such ulcers already present in the gastrointestinal tract.
  • the compounds are administered parenterally by injection or intravenous infusion in an infusion dose range of about 0.1 ⁇ g. to about 500 ⁇ g. per kg. of body weight per minute, or in a total daily dose by injection or infusion in the range of about 0.1 to about 20 mg. per kg. of body weight per day.
  • the PGE compounds are useful whenever it is desired to inhibit platelet aggregation, to reduce the adhesive character of platelets, and to remove or prevent the formation of thrombi in mammals, including man, rabbits, and rats. [Emmons et al., Brit. Med. J., 2: 468-472, 1967.] These compounds are, for example, useful in the treatment and prevention of mycardial infarcts, to treat and prevent post-operative thrombosis, to promote patency of vascular grafts following surgery, and to treat conditions such as atherosclerosis, arteriosclerosis, blood clotting defects due to lipemia, and other clinical conditions in which the underlying etiology is associated with lipid imbalance or hyperlipidemia. For these purposes, these compounds are administered systemically. For rapid response, especially in emergency situation, the intravenous route of administration is preferred. Doses in the range of about 0.005 to about 20 mg. per kg. of body weight per day are used.
  • the PGE compounds are especially useful as additives to blood, blood products, blood substitutes, and other fluids which are used in artificial extracorporeal circulation and perfusion of isolated body portions, e.g., limbs and organs, whether attached to the original body, detached and being preserved or prepared for transplant, or attached to the new body. Under such conditions, aggregated platelets tend to block the blood vessels and portions of the circulation apparatus. Such aggregation is inhibited by the presence of a prostaglandin.
  • the compound is added gradually or in single or multiple portions to the circulating blood, to the blood of the donor animal, to the perfused body portion, attached or detached, to the recipient, or to two or all of those at a total steady state dose of about 0.001 to 10 mg. per liter or circulating fluid.
  • PGE and PGF.sub. ⁇ compounds are extremely potent in causing stimulation of smooth muscle, and are also highly active in potentiating other known smooth muscle stimulators. Therefore, PGE 2 , for example, is useful in place of or in combination with less than usual amounts of these known smooth muscle stimulators, for example, to relieve the symptoms of paralytic ileus, or to control or prevent atonic uterine bleeding after abortion or delivery, to aid in expulsion of the placenta, and during the puerperium.
  • the PGE compound is administered intravenously immediately after abortion or delivery at a dose in the range of about 0.01 to about 50 ⁇ g. per kg. of body weight per minute until the desired effect is obtained. Subsequent doses are given parenterally during puerperium in the range 0.01 to 2 mg. per kg. of body weight per day.
  • the PGE, PGA and PGF.sub. ⁇ compounds are useful as hypotensive agents and vasodilators [Bergstrom et al., Acta. Physiol. Scand., 64: 332-333, 1965; Life Sci., 6:449-455, 1967] in mammals, including man.
  • the compounds are administered by intravenous infusion at the rate of about 0.01 to about 50 ⁇ g. per kg. of body weight per minute, or in single or multiple doses of about 25 to 500 ⁇ g. per kg. of body weight total per day.
  • the PGA and PGE compounds and derivatives and salts thereof increase the flow of blood in the mammalian kidney, thereby increasing volume and electrolyte content of the urine. For that reason, the compounds are useful in managing cases of renal disfunction, especially in cases of severely impaired renal blood flow, for example, the hepatorenal syndrome and early kidney transplant rejection. In cases of excessive or inappropriate ADH (antidiuretic hormone; vasopressin) secretion, the diuretic effect of these compounds is even greater. In anephretic states, the vasopressin action of these compounds is especially useful.
  • the compounds are useful in alleviating and correcting cases of edema resulting from massive surface burns, in the management of shock, etc.
  • the compounds are preferably first administered by intravenous injection at a dose in the range 10 to 1000 ⁇ g. per kg. of body weight or by intravenous infusion at a dose in the range 0.1 to 20 ⁇ g. per kg. of body weight per minute until the desired effect is obtained. Subsequent doses are given by intravenous, intramuscular, or subcutaneous injection or infusion in the range 0.05 to 2 mg. per kg. of body weight per day.
  • the PGE compounds are useful in the treatment of psoriasis (Ziboh, et. al., Nature, 254, 351 (1975)).
  • the compound is administered topically at a dose of 1-500 ⁇ g. 1 to 4 times daily until the desired effect is obtained.
  • the PGE especially PGE 2 , PGF.sub. ⁇ , and PGF.sub. ⁇ compounds are useful in the induction of labor in pregnant female animals, including man, cows, sheep, and pigs, at or near term [Karim et at., J. Obstet. Gynaec. Brit. Cwlth., 77:200-210, 1970] or in the induction of therapeutic abortion [Bygdeman et al., Contraception, 4, 293 (1971)].
  • the compound is infused intravenously at a dose of 0.01 to 50 ⁇ g. per kg. of body weight per minute until or near the termination of the second stage of labor, i.e., expulsion of the fetus.
  • These compounds are especially useful when the female is one or more weeks post-mature and natural labor has not started, or 12 to 60 hours after the membranes have ruptured and natural labor has not yet started.
  • Alternative routes of administration are oral, extraammiotic or intraammiotic.
  • the PGE, PGF.sub. ⁇ , and PGF.sub. ⁇ compounds are useful for fertility control in female mammals [Karim, Contraception, 3, 173 (1971)] including humans and animals such as monkeys, rats, rabbits, dogs, cattle, and the like.
  • ovulating female mammals animals which are mature enough to ovulate but not so old that regular ovulation has ceased.
  • PFG 2 ⁇ for example, is administered systemically at a dose level in the range 0.01 mg. to about 20 mg. per kg. of body weight of the female mammal, advantageously during a span of time starting approximately at the time of ovulation and ending approximately at the time of menses or just prior to menses.
  • Intravaginal and intrauterine are alternative routes of administration. Additionally, expulsion of an embryo or a fetus is accomplished by similar administration of the compound during the first third of the normal mammalian gestation period.
  • Patents have been obtained for several prostaglandins of the E and F series ad inducers of labor in mammals (Belgian Patent No. 754,158 and West German Patent No. 2,034,641), and one PGE 1 , E 2 and E 3 for control of the reproductive cycle (South African Patent No. 69/6089). It has been shown that luteolysis can take place as a result of administration of PGF 2 ⁇ [Labhsetwar, Nature, 230, 528 (1971)] and hence prostaglandins have utility for fertility control by a process in which smooth muscle stimulation is not necessary.
  • the PGE and PGF.sub. ⁇ compounds are useful as antiarrhythmic agents (Forster, et. al., Prostaglandins, 3, 895 (1973)).
  • the compound is infused intravenously at a dose range of 0.5-500 ⁇ g/kg/minute until the desired effect is obtained.
  • the PGE compounds are potent antagonists of epinephrine-induced mobilization of free fatty acids. For this reason, these compounds are useful in experimental medicine for both in vitro and in vivo studies in mammals, including man, rabbits, and rats, intended to lead to the understanding, prevention, symptom alleviation, and cure of diseases involving abnormal lipid mobilization and high free fatty acid levels, e.g., diabetes mellitus, vascular diseases, and hyperthyroidism.
  • diseases involving abnormal lipid mobilization and high free fatty acid levels e.g., diabetes mellitus, vascular diseases, and hyperthyroidism.
  • the PGE and PGB compounds promote and accelerate the growth of epidermal cells and keratin in animals, including humans, useful domestic animals, pets, zoological specimens, and laboratory animals. For that reason, these compounds are useful in promoting healing of skin which has been damaged, for example, by burns, wounds, and abrasions, surgery, etc. These compounds are also useful in promoting adherence and growth of skin autografts, especially small, deep (Davis) grafts which are intended to cover skinless areas by subsequent outward growth rather than initially, and to retard rejection of homografts.
  • skin autografts especially small, deep (Davis) grafts which are intended to cover skinless areas by subsequent outward growth rather than initially, and to retard rejection of homografts.
  • these compounds are preferably administered topically at or near the site where cell growth and keratin formation is desired, advantageously as an aerosol liquid or micronized powder spray, as an isotonic aqueous solution in the case of wet dressings, or as a lotion, cream, or ointment in combination with the usual pharmaceutically acceptable diluents.
  • systemic administration is advantageous.
  • these prostaglandins may be advantageously combined with antibiotics such as gentamycin, neomycin, polymyxin B, bacitracin, spectinomycin, tetracycline and oxytetracycline; with other antibacterials such as mafenide hydrochloride, sulfadiazine, furazolium chloride, and nitrofurazone; and with corticosteroids such as hydrocortisone, prednisolone, methylprednisolone, and fluprednisolone, each being used in the combination at the usual concentration suitable for its use alone.
  • antibiotics such as gentamycin, neomycin, polymyxin B, bacitracin, spectinomycin, tetracycline and oxytetracycline
  • other antibacterials such as mafenide hydrochloride, sulfadiazine, furazolium chloride, and nitrofurazone
  • corticosteroids such as hydrocortis
  • the particularly novel aspect of the compounds of the present invention is the termination of the top side chain with a carboxythiophene group. Though other modifications of the top side chain are known, they are by no means as common as modifications of the lower side chain.
  • Belgian Patent No. 816,566 shows 11-desoxy prostaglandins with a 2,5-furylene, phenylene or oxaphenylene group next to the carboxy group in the top side chain; no modification of the lower side chain is shown.
  • the West German Offenlegungsschrift No. 2,209,990 based in U.S. Ser. No. 121,572, filed Mar.
  • optically active compounds of the structure: ##STR11## Their optical antipodes and their racemic mixtures in which there is a cis double bond at the 5-position and Z is a trans double bond or a single bond.
  • M and X are selected from the group consisting of keto, ##STR12##
  • L is selected from the group consisting of hydrogen and hydroxyl.
  • R is selected from the group consisting of hydrogen, alkyl of from one to ten carbon atoms, cycloalkyl of from three to eight carbon atoms, phenyl, phenylalkyl of from seven to nine carbon atoms and mono-substituted phenyl wherein the substituent is selected from the group consisting of fluoro, chloro, bromo, iodo, alkyl and alkoxy of from one to six carbon atoms, and phenyl.
  • Ar is selected from the group consisting of phenyl, ⁇ -naphthyl, ⁇ -naphthyl and monosubstituted phenyl wherein the substituent is selected from the group consisting of fluoro, chloro, bromo, trifluoromethyl, phenyl and alkyl and alkoxy of from one to six carbon atoms.
  • the compounds of the present invention are particularly useful for their ability to induce spasms in the smooth muscle of the uterus and other smooth muscle.
  • the spasmogenic activity of the compounds of the present invention are of the order of the activities of PGF 2 and PGF 2 ⁇ , the present compounds are particularly useful because they have an extremely narrow activity spectrum.
  • the compounds of the present invention are principally smooth muscle stimulants. Other activities exhibited by the natural prostaglandins such as the ability to induce diarrhea, lower systemic blood pressure, dilate bronchioles and inhibit gastric secretion are relatively greatly diminished in the present invention. Nevertheless, their activity as smooth muscle stimulants remains relatively high. The same statements may be made of these compounds if they are compared with 16-aryloxy compounds which do not have a carboxythiophene group terminating the upper side chain.
  • optically active compounds of the structure ##STR13## Their optical antipodes and racemic mixtures thereof.
  • Ar, Z, R and X are as defined above.
  • Q is hydrogen or tetrahydropyran-2-yloxy and THP is tetrahydropyran-2-yl.
  • the wavy line at the 15-position indicates that the tetrahydropyran-2-yloxy group may be attached in either the ⁇ - or the ⁇ -configuration.
  • the above compounds are compounds that are converted into pharmaceutically active prostaglandins with a keto or ⁇ - or ⁇ -hydroxy group at each of the 9- and 15-positions and an ⁇ -hydroxy group or a hydrogen atom at the 11 ⁇ -position.
  • Another useful intermediate in the synthesis of the compounds of the present invention is the phosphonium salt of the structure: ##STR14## in which X is chloro, bromo or iodo.
  • the first step in the synthesis of the 11-desoxy compounds of the present invention is a condensation between the known aldehyde 1 (Corey and Ravindranathan, Tetrahedron Lett., 1971, 4753) with an appropriate 3-keto phosphonate to produce enone 2.
  • the keto phosphonate is usually produced by condensation of the appropriate carboxylic acid ester with a dialkyl methyl phosphonate. Typically the desired methyl ester is condensed with dimethyl methyl phosphonate.
  • Enone 2 is then reduced to enol 3 with zinc borohydride or a hindered alkyl borohydride such as lithium triethylborohydride or potassium tri-sec-butylborohydride.
  • This reduction produces a mixture of epimers both of which may be used as substrates for further reactions.
  • the 3 is used to produce prostaglandin analogs having a ⁇ -hydroxyl at C 15 .
  • the epimer of 3 is used to produce prostaglandin analogs having a ⁇ -hydroxy at C 15 .
  • the mixture of C 15 epimers may be used to produce 15-keto prostaglandin analogs.
  • the epimers produced in the hydride reduction can be separated by column, preparative thin layer, or preparative high pressure liquid chromatography. In the reduction reaction ethers such as tetrahydrofuran or 1,2-dimethoxyethane or acetonitrile are usually employed as solvents.
  • Enone 2 may be reduced catalytically with hydrogen to ketone 6, a suitable starting material for the preparation of 13,14-dihydro prostaglandin analogs of the present invention.
  • This reduction may be achieved with either a homogeneous catalyst such as tris-tri-phenylphosphinerhodiumchloride or with a heterogeneous catalyst system such as platinum, palladium or rhodium.
  • a homogeneous catalyst such as tris-tri-phenylphosphinerhodiumchloride
  • a heterogeneous catalyst system such as platinum, palladium or rhodium.
  • Enone 2 may also be reduced with borohydride ion to produce a mixture of the alcohol 7 and its C 15 epimer in a single step or alternatively, enol 3 may be catalytically reduced to produce the same epimer mixture.
  • the phosphonium salt is prepared by contacting substantially equimolar amounts of triphenylphosphine and 5-bromomethylthiophene-2-carboxylic acid in a reaction-inert solvent such as acetonitrile at reflux temperatures until the reaction is substantially complete.
  • the precipitated product is collected by filtration and recrystallized from a minimum amount of a suitable solvent or solvent system such as ethanol:hexane and air dried.
  • 10 is then purified as above.
  • the conversion of 10 ⁇ 11 is an acid catalyzed hydrolysis of protecting group. Any acid may be used which does not cause destruction of the molecule in the course of the removal of the protecting group, however, this is accomplished most often by the use of 65% aqueous acetic acid.
  • the dimethyl-tert-butylsilyl protecting group may be removed by the action of tetraalkylammonium fluoride in a solvent such as tetrahydrofuran.
  • the product is purified as above.
  • 11 is an 11-desoxy-16-aryloxy- ⁇ -tetranorprostaglandin of the F 2 ⁇ series.
  • the prostaglandin analogs of the E 2 series of this invention (13) are prepared from intermediate 10 which may be oxidized by any reagent capable of oxidizing hydroxyl groups which does not attack double bonds. However, the Jones reagent is usually preferred.
  • the product is purified as above to produce intermediate 12.
  • Intermediate 12 may be converted into the prostaglandin analogs of the E 2 series (13) of this invention in the same manner as described for (10 ⁇ 11).
  • intermediate 12 may be reduced with sodium borohydride to a mixture of intermediates 15 and 10 which are separable by column, preparative thin layer, or preparative high pressure liquid chromatography and which can be converted into prostaglandin analogs of the F 2 ⁇ and F 2 ⁇ series of this invention by the methods given for (10 ⁇ 11).
  • compound 13 may be reduced with sodium borohydride to provide the F 2 ⁇ and F 2 ⁇ prostaglandin analogs of this invention directly.
  • This epimeric mixture may be separated as described above for 15 to provide pure PGF 2 ⁇ and PGF 2 ⁇ .
  • the enone 17 can be reduced with zinc borohydride or with trialkylborohydrides, such as lithium triethylborohydride, to a mixture of epimeric alcohols, which can be separated as above. Only the ⁇ epimer 18 is shown. If the ⁇ epimer is used in its place in the following synthesis, one will produce the corresponding 15 ⁇ -hydroxy prostaglandins. In this reaction ethers such as tetrahydrofuran or 1,2 dimethoxy ethane or acetonitrile are usually employed as solvents.
  • 18 ⁇ 19 is a base catalyzed transesterification in which the p-biphenyl-carbonyl protecting group is removed. This is most conveniently conducted with potassium carbonate in methanol or methanol-tetrahydrofuran solvent.
  • 19 ⁇ 20 involves the protection of the two free hydroxyl groups with an acid-labile protecting group. Any sufficiently acid-labile group is satisfactory; however, the most usual one is tetrahydropyranyl, which can be incorporated in the molecule by treatment with dihydropyran and an acid catalyst in an anhydrous medium.
  • the catalyst is usually p-toluenesulfonic acid.
  • 20 ⁇ 21 is a reduction of the lactone 20 to the hemiacetal 21 using diisobutyl aluminum hydride in an inert solvent.
  • Low reaction temperatures are preferred and -60° to -70° C. are usual. However, higher temperature may be employed if over-reduction does not occur.
  • 21 is purified, if desired, by column chromatography.
  • 21 ⁇ 22 is a Wittig condensation in which hemiacetal 21 is reacted with (2-carboxythiophen-5-ylmethyl)triphenylphosphonium bromide in dimethyl sulfoxide, in the presence of sodium methylsulfinyl methide. 22 is purified as above.
  • the conversion 22 ⁇ 25 is an acidic hydrolysis of the tetrahydropyranyl groups. Any acid may be used which does not cause destruction of the molecule in the course of the removal of the protecting groups, however, this is acomplished most often by use of 65% aqueous acetic acid.
  • the product is purified as above.
  • the 22 ⁇ 23 is an oxidation of the secondary alcohol 22 to the ketone 23. This may be accomplished using any oxidizing agent which does not attack double bonds; however, the Jones reagent is usually preferred.
  • the product is purified as above.
  • the 15-keto compounds of the present invention are prepared dissolving the corresponding PGE 2 or PGF 2 compound in a reaction-inert solvent such as benzene or toluene.
  • a reaction-inert solvent such as benzene or toluene.
  • manganese dioxide is added in an amount approximately one to ten times the weight of the prostaglandin and the reaction stirred at a temperature of from about 10° to 80° C. until the reaction is substantially complete.
  • the reaction mixture is then filtered and evaporated to yield the crude product which is purified by column chromatography.
  • the 13,14-dihydro PGE 2 or PGF 2 ⁇ compounds of the present invention are prepared from the hemiacetal 26 following procedures already outlined by the conversion of 21 into 25, 24 and 27.
  • the hemiacetal 26 may be prepared from 17, 18, 19 or 20 as described above. ##STR20##
  • the PGF 62 compounds of the present invention may be prepared from 23 or 24 by procedures described above for 12 or 13 into 14.
  • the assignment of the configuration of C15 is made on the basis of mobilities in thin layer chromatography of the alcohols 3 and C15-epi-3 and 18 and C 15 -epi-18. It is assumed that the less polar (higher R f ) epimer has the 15 ⁇ -hydroxy configuration and the more polar (lower R f ) epimer has the 15 ⁇ -hydroxy configuration.
  • suitable solvent systems are mixtures of ether or ethyl acetate in benzene. This assignment of C 15 configuration is based on that observed for the synthesis of the natural prostaglandins (Corey, et al., J. Am. Chem. Soc., 93, 1491 (1971).
  • the assignment of the configuration of C 9 is made on the basis of mobilities in thin layer chromatography of the alcohols 11 and 14 and 25 and 27. It is assumed that the less polar (higher R f ) epimer has the 9 ⁇ -hydroxy configuration and the more polar (lower R f ) epimer has the 9 ⁇ -hydroxy configuration.
  • suitable solvent systems are mixtures of methylene chloride or chloroform and methanol. This assignment of C 9 configuration is based on analogy with the natural prostaglandins (Green and Samuelsson, J. Lipid Res., 5, 1A (1964)).
  • Phenyl and substituted phenyl esters of the present invention are prepared by contacting a prostanoic acid with an appropriate phenol in reaction-inert solvent such as dry methylene chloride in the presence of a coupling agent such as dicyclohexylcarbodiimide or diethylcarbodiimide.
  • a coupling agent such as dicyclohexylcarbodiimide or diethylcarbodiimide.
  • 5-(carboxythiophen-2-yl)-9-oxo-11 ⁇ ,15 ⁇ -dihydroxy-16-phenoxy-cis-5-trans-13 ⁇ -tetranor- ⁇ -tetranorprostadienoic acid may be contacted with p-phenylphenol in dry methylene chloride in the presence of dicyclohexylcarbodiimide to form the corresponding ester.
  • Alkyl and phenylalkyl esters of the present invention may be prepared by contacting a prostanoic acid with an appropriate diazoalkane in a reaction-inert solvent such as ether or tetrahydrofuran.
  • the esters of the present invention may be prepared by first contacting a prostanoic acid with pivaloyl chloride in a reaction inert solvent such as ether in the presence of an appropriate base such as triethylamine and then treating the resultant intermediate with an appropriate alcohol.
  • chromatographic supports include neutral alumina and silica gel.
  • the chromatography is suitably conducted in reaction-inert solvents such as ether, ethyl acetate, benzene, chloroform, methylene chloride, cyclohexane and n-hexane, as further illustrated in the appended examples.
  • reaction-inert solvents such as ether, ethyl acetate, benzene, chloroform, methylene chloride, cyclohexane and n-hexane, as further illustrated in the appended examples.
  • appropriate supports include ⁇ Corasil ⁇ , ⁇ Porasil ⁇ , and ⁇ Lichrosorb ⁇ with inert solvents such as ether, chloroform, methylenechloride, cyclohexane and n-hexane being employed.
  • the physiological responses observed in these tests are useful in determining the utility of the test substance for the treatment of various natural and pathological conditions.
  • Such determined utilities include: vasodilator activity, antihypertensive activity, bronchodilator activity, antiarrythmic activity, cardiac stimulant activity, antifertility activity, antiulcer activity and antisecretory activity.
  • An advantage possessed by 11-desoxy prostaglandins of the E series in general is their increased stability as compared with such as PGE 2 .
  • the novel prostaglandin analogs of this invention possess highly selective activity profiles compared with the corresponding naturally occurring prostaglandins and, in many cases, exhibit a longer duration of action.
  • the novel prostaglandin analogs of this invention possess useful antifertility activity.
  • Pharmacologically acceptable salts useful for the purposes described above are those with pharmacologically acceptable metal cations, ammonium, amine cations, or quaternary ammonium cations. Salts can be formed with the acids of the present invention.
  • Especially preferred metal cations are those derived from the alkali metals, e.g., lithium, sodium and potassium, and from the alkaline earth metals, e.g., magnesium and calcium, although cationic forms of other metals, e.g., aluminum, zinc, and iron, are within the scope of this invention.
  • amine cations are those derived from primary, secondary, or tertiary amines.
  • suitable amines are methylamine, dimethylamine, triethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, ⁇ -phenylethylamine, ⁇ -phenylethylamine, ethylenediamine, diethylenetriamine, and like aliphatic, cycloaliphatic, and araliphatic amines containing up to and including about 18 carbon atoms, as well as heterocyclic amines, e.g., piperidine, morpholine, pyrrolidine, piperazine, and lower-alkyl derivatives thereof, e.g., 1-
  • Suitable pharmacologically acceptable quaternary ammonium cations are tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, phenyltriethylammonium and the like.
  • the new compounds of this invention can be used in a variety of pharmaceutical preparations which contain the compound or a pharmaceutically acceptable salt thereof, and they may be administered in the same manner as natural prostaglandins by a variety of routes, such as intravenous, oral and topical, including aerosol, intravaginal, and intranasal, among others.
  • routes such as intravenous, oral and topical, including aerosol, intravaginal, and intranasal, among others.
  • tablets or an aqueous suspension or alcoholic solution of a compound of the present invention would appropriately be administered at oral doses of about 0.1-20 mg., with 1-7 doses per day being employed.
  • a suitable formulation would be lactose tablets or an impregnated tampon of the same agent.
  • suitable doses would be from about 0.1-20 mg/dose with 1-7 doses being employed.
  • a suitable formulation would be an aqueous solution containing 0.05-10 mg/dose with 1-7 doses being employed.
  • a suitable formulation would be an aqueous solution containing 0.005-1 mg/dose with 1-5 doses being employed.
  • these compounds can be infused intravenously for induction of abortion at doses of 0.05-50 ⁇ g/minute for a period of from about 1-24 hours.
  • Another use for the novel compounds of the present invention is as an inducer of labor.
  • an ethanol-saline solution is employed as an intravenous infusion in the amount of from about 0.1-10 ⁇ g/kg/min for from about 1-24 hours.
  • a tablet is employed for intravaginal or oral administration containing 0.1-20 mg. of prostaglandin per dose with 1-7 doses being employed at or following the expected day of menstruation.
  • a solution or suspension containing 0.03-30 mg/dose of the compound is administered intramuscularly from 1-4 days.
  • reaction-inert diluents include, for example, water, ethanol, gelatins, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, petroleum jelly, cholesterol, and other known carriers for medicaments.
  • these pharmaceutical compositions may contain auxiliary substances such as preserving agents, wetting agents, stabilizing agents, or other therapeutic agents such as antibiotics.
  • the ir spectrum (KBr) of the product exhibited absorption bands at 1775 cm -1 (strong), 1715 cm -1 (strong), 1675 cm -1 (medium) and 1630 cm -1 (medium) attributable to the carbonyl groups and at 970 cm -1 for the trans double bond.
  • Example II the phosphonates of Example II may be reacted with the ⁇ lacetone aedehyde.
  • Example III may be reduced with zinc borohydride.
  • the 15-epi product of this Example may be converted into the 15-eip prostaglandin analogs of this invention by the procedures of Examples V-VII, IX-XII ⁇ XVII-XX, and XXI°.
  • Example IV In a similar fashion, one may solvolyze the other compounds of Example IV.
  • Example V The other compounds of Example V may, in a similar fashion, be contacted with 2,3-dihydropyran.
  • Example XXIV The product of this Example may be catalytically hydrogenated by the procedure of Example XXIV to provide 2-[5 ⁇ -hydroxy-3 ⁇ -(tetrahydropyran-2-yloxy)-2 ⁇ -(3 ⁇ -(tetrahydropyran-2-yloxy)-4-phenoxybut-1-yl)cyclopent-1 ⁇ -yl]acetic acid, ⁇ -lactone which may be converted into the 13,14 -dihydroprostaglandin two-series analogs of this invention by the procedures of Examples VII, IX-XII, XVII-XX and XI-XXII.
  • Example VI One may reduce the other compounds of Example VI in a similar fashion with diisobutylaluminum hydride.
  • the ir spectrum (CHCl 3 ) of the purified product exhibited a strong absorption at 1710 cm -1 for the acid carbonyl and a medium absorption at 970 cm -1 for the trans double bond.
  • Example VII may be contacted with (2-carboxythiophen-5-yl-methyl)triphenylphosphonium bromide.
  • Example IX The other compounds of Example IX are solvolyzed in a similar fashion.
  • Example IX The other compounds of Example IX may be oxidized in a similar fashion.
  • Example XXI The product of this Example may be reduced by the procedure of Example XXI and then hydrolyzed by the procedure of Example X to form the prostaglandin F 2 ⁇ analogs of this invention.
  • Example XI The other compounds of Example XI may be solvolyzed in a similar manner.
  • the ir spectrum (CHCl 3 ) of the product exhibited absorption bands at 1775 cm -1 (strong), 1715 cm -1 (strong), 1675 cm -1 (medium) and 1630 cm -1 (medium) attributable to the carbonyl groups and at 970 cm -1 for the trans double bond.
  • reaction mixture was concentrated by rotary evaporation, taken up in ether and washed with 100 ml. water (2x) and 100 ml. brine (2x). After drying (Na 2 SO 4 ) and concentrating the resultant oil was purified by column chromatography on silica gel (Baker "Analyzed” Reagent) using ether as eluent. After elution of less polar impurities, a fraction "containing 1.5 g 2-[5 ⁇ -hydroxy-2 ⁇ -(3 ⁇ -hydroxy-4-(m-tolyloxy)-trans-1 -buten-1-yl) cyclopent-1 ⁇ -yl]acetic acid, ⁇ -lactone (3), a 400 mg.
  • Example XIII may be reduced to an epimeric mixture of 3-hydroxy compounds which may be separated by column chromatography.
  • the 15-epi product of this Example may be converted into the 11-desoxy-15-epi prostaglandin analog of this invention by the procedures of XV, XVI, IX-XII, and XVII-XXIII.
  • the ir (CHCl 3 ) spectrum had a medium absorbtion at 970 cm -1 for the trans double bond and at 1770 cm -1 for the lactone carbonyl.
  • Example XIV may be reacted with 2,3-dihydropyran.
  • Example XV may be converted to ⁇ -hemiacetals.
  • Example IX-XII and XVII-XXIII may be converted into the 11-desoxy PGE 2 and PGF 2 analogs of the present invention.
  • the solid residue is purified by silica gel (Baker "Analyzed”60-200 mesh) chromatography using mixtures of chloroform:benzene as eluents. After removal of less polar impurities the title compound is eluted.
  • these acids may be converted to other aryl esters by employing, among others, the following phenols
  • the compounds of Examples X, XII, XVI and XXI-XXIII may be converted to their decyl esters.
  • the other alkyl, cycloalkyl and phenylalkyl esters of the present invention may be prepared by treating the appropriate prostadienoic acid with the desired diazo compound which is prepared by oxidation of the corresponding hydrazine.
  • Examples X, XII, XVI, and XXI-XXIII may be converted to their cyclooctyl esters.
  • the other alkyl, cycloalkyl and phenylalkyl esters of the present invention may be prepared by employing the appropriate alkanol.
  • the ethyl acetate layer is washed with water (2 ⁇ 10 ml) and saturated brine (10 ml), is dried (sodium sulfate) and is concentrated.
  • the crude residue is purified by silica gel column chromatography to provide first 5-(2-carboxythiophen-5-yl)-11 ⁇ ,9 ⁇ ,15 ⁇ -trihydroxy-16-phenyloxy- ⁇ -tetranor- ⁇ -tetranorprostanoic acid, a mixture of C 9 epimers, and finally 9 ⁇ ,5-(2-carboxythiophen-5 -yl)11 ⁇ ,15 ⁇ -trihydroxy-16-phenyloxy- ⁇ -tetranor- ⁇ -tetranorprostanoic acid.
  • Examples X and XII may be converted into the 15-keto PGE 2 and PGF 2 ⁇ analogs of the present invention.
  • the product of this example may be converted into the 13,14-dihydroprostaglandin two-series analogs of this invention by the procedures of Examples VII, IX-XII and XVII-XXII.

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US05/617,481 1975-09-29 1975-09-29 5-(2-Carboxythiophen-5-yl)-16-aryloxy-α-tetranor-ω-tetranorprostaglandins Expired - Lifetime US4065472A (en)

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US05/617,481 US4065472A (en) 1975-09-29 1975-09-29 5-(2-Carboxythiophen-5-yl)-16-aryloxy-α-tetranor-ω-tetranorprostaglandins
IE1704/76A IE44067B1 (en) 1975-09-29 1976-07-30 1,5-inter-(2,5-thienylene)-2,3,4,17,18,19,20-heptanoprostaglandins
DE2640692A DE2640692C3 (de) 1975-09-29 1976-09-10 Optisch aktive 5- (2-Carboxythiophen5-yl)-16phenoxy- a -tetranor- w tetranor-prostaglandine
GB38949/76A GB1508925A (en) 1975-09-29 1976-09-20 1,5-inter-(2,5-thienylene)-2,3,4,17,18,19,20-heptanorprostaglandins
CA261,914A CA1085832A (en) 1975-09-29 1976-09-23 Prostaglandin analogs
BE1007651A BE846650A (fr) 1975-09-29 1976-09-28 Homologues de prostaglandines
DK435276A DK435276A (da) 1975-09-29 1976-09-28 Fremgangsmade til fremstilling af prostaglandin-analoge og mellemprodukter til brug herved
JP51117079A JPS5242872A (en) 1975-09-29 1976-09-29 Novel homologue of natural prostaglandine
FR7629245A FR2325371A1 (fr) 1975-09-29 1976-09-29 Homologues de prostaglandines
LU75904A LU75904A1 (US20030199744A1-20031023-C00003.png) 1975-09-29 1976-09-29
NL7610761A NL7610761A (nl) 1975-09-29 1976-09-29 Werkwijze voor de bereiding van prostaglandinen en van preparaten die ze bevatten.
DK163879A DK163879A (da) 1975-09-29 1979-04-20 15-tetrahydropyranyloxyprostensyre-derivater til anvendelse som mellemprosukter ved fremstilling af prostaglandin-analoge

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US5378451A (en) * 1989-10-19 1995-01-03 Dow B. Hickam, Inc. Topical medicinal pressurized aerosol compositions and method of preparation, method of use and article of manufacture thereof

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GB1350971A (en) 1971-05-11 1974-04-24 Imp Chemi Als Ind Ltd Cyclopentane derivatives
US3922289A (en) * 1973-02-23 1975-11-25 Syntex Inc Trans-prostaglandin-like compounds and methods

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1350971A (en) 1971-05-11 1974-04-24 Imp Chemi Als Ind Ltd Cyclopentane derivatives
US3922289A (en) * 1973-02-23 1975-11-25 Syntex Inc Trans-prostaglandin-like compounds and methods

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5378451A (en) * 1989-10-19 1995-01-03 Dow B. Hickam, Inc. Topical medicinal pressurized aerosol compositions and method of preparation, method of use and article of manufacture thereof

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